WO2023246701A1 - Anticorps et son utilisation - Google Patents
Anticorps et son utilisation Download PDFInfo
- Publication number
- WO2023246701A1 WO2023246701A1 PCT/CN2023/101086 CN2023101086W WO2023246701A1 WO 2023246701 A1 WO2023246701 A1 WO 2023246701A1 CN 2023101086 W CN2023101086 W CN 2023101086W WO 2023246701 A1 WO2023246701 A1 WO 2023246701A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- seq
- sequence shown
- cdr
- cdrs
- following
- Prior art date
Links
- 238000009739 binding Methods 0.000 claims abstract description 166
- 230000027455 binding Effects 0.000 claims abstract description 165
- 239000000427 antigen Substances 0.000 claims abstract description 159
- 108091007433 antigens Proteins 0.000 claims abstract description 159
- 102000036639 antigens Human genes 0.000 claims abstract description 159
- 239000012634 fragment Substances 0.000 claims abstract description 141
- 102100035350 CUB domain-containing protein 1 Human genes 0.000 claims abstract description 93
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 78
- 238000000034 method Methods 0.000 claims abstract description 48
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
- 201000010099 disease Diseases 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 101000737742 Homo sapiens CUB domain-containing protein 1 Proteins 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 31
- 230000012202 endocytosis Effects 0.000 claims abstract description 24
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 12
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 10
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 10
- 210000004027 cell Anatomy 0.000 claims description 135
- 241000282414 Homo sapiens Species 0.000 claims description 46
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 29
- 239000013543 active substance Substances 0.000 claims description 28
- 238000010168 coupling process Methods 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 24
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 23
- 150000001413 amino acids Chemical class 0.000 claims description 23
- 230000008878 coupling Effects 0.000 claims description 23
- 238000005859 coupling reaction Methods 0.000 claims description 23
- 210000003236 esophagogastric junction Anatomy 0.000 claims description 22
- 206010006187 Breast cancer Diseases 0.000 claims description 21
- 208000026310 Breast neoplasm Diseases 0.000 claims description 21
- 238000005516 engineering process Methods 0.000 claims description 19
- 230000014509 gene expression Effects 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 19
- 206010009944 Colon cancer Diseases 0.000 claims description 18
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 17
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 239000013598 vector Substances 0.000 claims description 17
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 16
- 206010060862 Prostate cancer Diseases 0.000 claims description 16
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 16
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 16
- 201000005202 lung cancer Diseases 0.000 claims description 16
- 208000020816 lung neoplasm Diseases 0.000 claims description 16
- 238000002560 therapeutic procedure Methods 0.000 claims description 16
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 108090000790 Enzymes Proteins 0.000 claims description 14
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 14
- 206010033128 Ovarian cancer Diseases 0.000 claims description 14
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 14
- 206010038389 Renal cancer Diseases 0.000 claims description 14
- 201000010982 kidney cancer Diseases 0.000 claims description 14
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 13
- 238000000684 flow cytometry Methods 0.000 claims description 13
- 210000002865 immune cell Anatomy 0.000 claims description 13
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 13
- -1 nuclides Substances 0.000 claims description 13
- 201000002528 pancreatic cancer Diseases 0.000 claims description 13
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 13
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 12
- 239000012190 activator Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 206010017758 gastric cancer Diseases 0.000 claims description 12
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 12
- 201000011549 stomach cancer Diseases 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 11
- 206010005003 Bladder cancer Diseases 0.000 claims description 11
- 206010005949 Bone cancer Diseases 0.000 claims description 11
- 208000018084 Bone neoplasm Diseases 0.000 claims description 11
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 11
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 11
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 11
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 11
- 206010027406 Mesothelioma Diseases 0.000 claims description 11
- 208000034578 Multiple myelomas Diseases 0.000 claims description 11
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims description 11
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 11
- 206010039491 Sarcoma Diseases 0.000 claims description 11
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 11
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 11
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 11
- 206010057644 Testis cancer Diseases 0.000 claims description 11
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 11
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 11
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 11
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 11
- 208000009956 adenocarcinoma Diseases 0.000 claims description 11
- 201000010881 cervical cancer Diseases 0.000 claims description 11
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 11
- 201000004101 esophageal cancer Diseases 0.000 claims description 11
- 201000010175 gallbladder cancer Diseases 0.000 claims description 11
- 201000003115 germ cell cancer Diseases 0.000 claims description 11
- 208000005017 glioblastoma Diseases 0.000 claims description 11
- 201000010536 head and neck cancer Diseases 0.000 claims description 11
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 11
- 201000005787 hematologic cancer Diseases 0.000 claims description 11
- 208000032839 leukemia Diseases 0.000 claims description 11
- 201000007270 liver cancer Diseases 0.000 claims description 11
- 208000014018 liver neoplasm Diseases 0.000 claims description 11
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 11
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 11
- 201000001441 melanoma Diseases 0.000 claims description 11
- 201000000849 skin cancer Diseases 0.000 claims description 11
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 11
- 201000003120 testicular cancer Diseases 0.000 claims description 11
- 201000002510 thyroid cancer Diseases 0.000 claims description 11
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 11
- 206010046766 uterine cancer Diseases 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 10
- 230000012292 cell migration Effects 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 102000051487 human CDCP1 Human genes 0.000 claims description 9
- 241001529936 Murinae Species 0.000 claims description 8
- 238000009098 adjuvant therapy Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 7
- 238000007792 addition Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- 238000012217 deletion Methods 0.000 claims description 7
- 230000037430 deletion Effects 0.000 claims description 7
- 210000000987 immune system Anatomy 0.000 claims description 7
- 201000009377 thymus cancer Diseases 0.000 claims description 7
- 230000004565 tumor cell growth Effects 0.000 claims description 7
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 6
- 238000002965 ELISA Methods 0.000 claims description 6
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 238000009099 neoadjuvant therapy Methods 0.000 claims description 6
- 102000015696 Interleukins Human genes 0.000 claims description 5
- 108010063738 Interleukins Proteins 0.000 claims description 5
- 239000002254 cytotoxic agent Substances 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 239000003053 toxin Substances 0.000 claims description 5
- 231100000765 toxin Toxicity 0.000 claims description 5
- 108700012359 toxins Proteins 0.000 claims description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 4
- 239000012275 CTLA-4 inhibitor Substances 0.000 claims description 4
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 4
- 102000004127 Cytokines Human genes 0.000 claims description 4
- 108090000695 Cytokines Proteins 0.000 claims description 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 4
- 102000014150 Interferons Human genes 0.000 claims description 4
- 108010050904 Interferons Proteins 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 239000012270 PD-1 inhibitor Substances 0.000 claims description 4
- 239000012668 PD-1-inhibitor Substances 0.000 claims description 4
- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 4
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 4
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 4
- 238000009169 immunotherapy Methods 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 244000309459 oncolytic virus Species 0.000 claims description 4
- 229940121655 pd-1 inhibitor Drugs 0.000 claims description 4
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 3
- 230000006907 apoptotic process Effects 0.000 claims description 3
- 238000004113 cell culture Methods 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 2
- 241000282836 Camelus dromedarius Species 0.000 claims description 2
- 241000251730 Chondrichthyes Species 0.000 claims description 2
- 238000009007 Diagnostic Kit Methods 0.000 claims description 2
- 108090001005 Interleukin-6 Proteins 0.000 claims description 2
- 229930126263 Maytansine Natural products 0.000 claims description 2
- 238000002659 cell therapy Methods 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 238000003748 differential diagnosis Methods 0.000 claims description 2
- 238000001415 gene therapy Methods 0.000 claims description 2
- 239000012651 immune agonist Substances 0.000 claims description 2
- 229940044680 immune agonist Drugs 0.000 claims description 2
- 229940047124 interferons Drugs 0.000 claims description 2
- 229940047122 interleukins Drugs 0.000 claims description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 claims description 2
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 2
- 108010059074 monomethylauristatin F Proteins 0.000 claims description 2
- 230000017074 necrotic cell death Effects 0.000 claims description 2
- 108010067988 prolactin-binding protein Proteins 0.000 claims description 2
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 claims 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims 1
- 108010000912 Egg Proteins Proteins 0.000 claims 1
- 102000002322 Egg Proteins Human genes 0.000 claims 1
- 102000006992 Interferon-alpha Human genes 0.000 claims 1
- 108010047761 Interferon-alpha Proteins 0.000 claims 1
- 229940044683 chemotherapy drug Drugs 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 235000014103 egg white Nutrition 0.000 claims 1
- 210000000969 egg white Anatomy 0.000 claims 1
- 230000036039 immunity Effects 0.000 claims 1
- 229960003444 immunosuppressant agent Drugs 0.000 claims 1
- 239000003018 immunosuppressive agent Substances 0.000 claims 1
- 239000000941 radioactive substance Substances 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- 230000005012 migration Effects 0.000 abstract description 6
- 238000013508 migration Methods 0.000 abstract description 6
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 157
- 101710082365 CUB domain-containing protein 1 Proteins 0.000 description 71
- 238000001514 detection method Methods 0.000 description 45
- 239000000562 conjugate Substances 0.000 description 37
- 108090000623 proteins and genes Proteins 0.000 description 34
- 108090000765 processed proteins & peptides Proteins 0.000 description 29
- 230000000694 effects Effects 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 26
- 102000004196 processed proteins & peptides Human genes 0.000 description 25
- 102000004169 proteins and genes Human genes 0.000 description 25
- 229920001184 polypeptide Polymers 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 24
- 229940024606 amino acid Drugs 0.000 description 22
- 241000699666 Mus <mouse, genus> Species 0.000 description 19
- 125000000539 amino acid group Chemical group 0.000 description 15
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 229940088598 enzyme Drugs 0.000 description 13
- 229940049595 antibody-drug conjugate Drugs 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 210000003719 b-lymphocyte Anatomy 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 108010004729 Phycoerythrin Proteins 0.000 description 10
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 210000004408 hybridoma Anatomy 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 230000004927 fusion Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 238000004422 calculation algorithm Methods 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 6
- 230000005593 dissociations Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 230000002163 immunogen Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000282567 Macaca fascicularis Species 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 238000003018 immunoassay Methods 0.000 description 5
- 210000003712 lysosome Anatomy 0.000 description 5
- 230000001868 lysosomic effect Effects 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000009870 specific binding Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- OBYNJKLOYWCXEP-UHFFFAOYSA-N 2-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]-4-isothiocyanatobenzoate Chemical compound C=12C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C2C=1C1=CC(N=C=S)=CC=C1C([O-])=O OBYNJKLOYWCXEP-UHFFFAOYSA-N 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 201000009365 Thymic carcinoma Diseases 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000006143 cell culture medium Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 235000002374 tyrosine Nutrition 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 108090001008 Avidin Proteins 0.000 description 3
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 101100112830 Mus musculus Cdcp1 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 101000804877 Schizosaccharomyces pombe (strain 972 / ATCC 24843) 5'-3' exoribonuclease 1 Proteins 0.000 description 3
- 102000002689 Toll-like receptor Human genes 0.000 description 3
- 108020000411 Toll-like receptor Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000021164 cell adhesion Effects 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 210000004180 plasmocyte Anatomy 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 239000004366 Glucose oxidase Substances 0.000 description 2
- 108010015776 Glucose oxidase Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 108010046334 Urease Proteins 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 2
- 210000004507 artificial chromosome Anatomy 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000005880 cancer cell killing Effects 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 230000008045 co-localization Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 229940116332 glucose oxidase Drugs 0.000 description 2
- 235000019420 glucose oxidase Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 229960003742 phenol Drugs 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 239000002096 quantum dot Substances 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000001370 static light scattering Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 2
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 2
- 235000008521 threonine Nutrition 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 1
- HXUVTXPOZRFMOY-NSHDSACASA-N 2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]acetic acid Chemical compound NCC(=O)NCC(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 HXUVTXPOZRFMOY-NSHDSACASA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-N 0.000 description 1
- 101150085602 CDCP1 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 241000257465 Echinoidea Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 241001524679 Escherichia virus M13 Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101100112829 Homo sapiens CDCP1 gene Proteins 0.000 description 1
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102000012355 Integrin beta1 Human genes 0.000 description 1
- 108010022222 Integrin beta1 Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 102000004407 Lactalbumin Human genes 0.000 description 1
- 108090000942 Lactalbumin Proteins 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100025096 Mesothelin Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 101100088247 Picea mariana RPL13A gene Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- YJQCOFNZVFGCAF-UHFFFAOYSA-N Tunicamycin II Natural products O1C(CC(O)C2C(C(O)C(O2)N2C(NC(=O)C=C2)=O)O)C(O)C(O)C(NC(=O)C=CCCCCCCCCC(C)C)C1OC1OC(CO)C(O)C(O)C1NC(C)=O YJQCOFNZVFGCAF-UHFFFAOYSA-N 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- BUBBEHCXSMCYNY-CVEARBPZSA-N [3-hydroxy-5-methyl-4-[(2S,3R)-2,3,4-trihydroxybutoxy]carbonylphenyl] 2,4-dihydroxy-6-methylbenzoate Chemical compound CC1=CC(O)=CC(O)=C1C(=O)OC1=CC(C)=C(C(=O)OC[C@H](O)[C@H](O)CO)C(O)=C1 BUBBEHCXSMCYNY-CVEARBPZSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical class C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229950009494 bropirimine Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002121 endocytic effect Effects 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- BUBBEHCXSMCYNY-UHFFFAOYSA-N erythrin Natural products CC1=CC(O)=CC(O)=C1C(=O)OC1=CC(C)=C(C(=O)OCC(O)C(O)CO)C(O)=C1 BUBBEHCXSMCYNY-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000010437 gem Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000005305 interferometry Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940127075 other antimetabolite Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- RXNXLAHQOVLMIE-UHFFFAOYSA-N phenyl 10-methylacridin-10-ium-9-carboxylate Chemical class C12=CC=CC=C2[N+](C)=C2C=CC=CC2=C1C(=O)OC1=CC=CC=C1 RXNXLAHQOVLMIE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000012743 protein tagging Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 210000003660 reticulum Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229960001147 triclofos Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- ZHSGGJXRNHWHRS-VIDYELAYSA-N tunicamycin Chemical compound O([C@H]1[C@@H]([C@H]([C@@H](O)[C@@H](CC(O)[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C(NC(=O)C=C2)=O)O)O1)O)NC(=O)/C=C/CC(C)C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O ZHSGGJXRNHWHRS-VIDYELAYSA-N 0.000 description 1
- MEYZYGMYMLNUHJ-UHFFFAOYSA-N tunicamycin Natural products CC(C)CCCCCCCCCC=CC(=O)NC1C(O)C(O)C(CC(O)C2OC(C(O)C2O)N3C=CC(=O)NC3=O)OC1OC4OC(CO)C(O)C(O)C4NC(=O)C MEYZYGMYMLNUHJ-UHFFFAOYSA-N 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
Definitions
- CUB domain-containing protein 1 also called cluster of differentiation (CD318), is a type I transmembrane glycoprotein that contains 2-3 CUB (Complement protein components C1 , Urchin embryonic growth factor and Bone morphogenic protein 1) Extracellular domain (Extracellular domain, ECD) and intracellular domain containing 5 tyrosines (Intracellular domain, ICD, Y707, Y734, Y743, Y762 and Y806) .
- CUB domain-containing protein 1 also called cluster of differentiation (CD318)
- Extracellular domain Extracellular domain
- ECD Extracellular domain
- intracellular domain containing 5 tyrosines Intrtracellular domain, ICD, Y707, Y734, Y743, Y762 and Y806 .
- the actual SDS-PAGE size is 135kDa or 140kDa (CDCP1 -135 or p140), may be related to glycosylation level.
- the extracellular region of CDCP1 can be hydrolyzed by serine protease near its Arg368 position into free CDCP1-65 of 70-80kDa (p80 or CDCP1-70) and 65kDa.
- the expression levels of p140 and p80 differ in different cells, mainly determined by the level of serine protease.
- CDCP1 mainly exists in the form of p140 that is not hydrolyzed, and hydrolysis of CDCP1 occurs only during tumorigenesis or tissue damage.
- CDCP1-p-Y734 levels were significantly increased in patients with lung cancer and gastric cancer. The test found that 60 or 200 lung cancer patients had moderate or high expression of CDCP1, and patients with high expression were more likely to develop lymph node metastasis and recurrence.
- the 5-year survival rate is even lower; a study of 230 renal cancer patients showed that CDCP1 expression is difficult to detect in normal tissues, while high CDCP1 expression can be detected in 33.5% of patient tissues.
- CDCP1 is highly expressed in lymphoma cells.
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:136, CDR-L2 containing the sequence shown in SEQ ID NO:171, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: CDR- containing the sequence shown in SEQ ID NO:2 H1, CDR-H2 comprising the sequence shown in SEQ ID NO:39, CDR-H3 comprising the sequence shown in SEQ ID NO:81; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:124, CDR-L2 containing the sequence shown in SEQ ID NO:164, and CDR-L2 containing the sequence shown in SEQ ID NO:197 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:125, CDR-L2 containing the sequence shown in SEQ ID NO:165, and CDR-L2 containing the sequence shown in SEQ ID NO:198 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:127, CDR-L2 containing the sequence shown in SEQ ID NO:168, and CDR-L2 containing the sequence shown in SEQ ID NO:201 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:128, CDR-L2 containing the sequence shown in SEQ ID NO:169, and CDR-L2 containing the sequence shown in SEQ ID NO:202 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: CDR-H1 containing the sequence shown in SEQ ID NO:6, CDR-H2 containing the sequence shown in SEQ ID NO:42, and CDR-H2 containing the sequence shown in SEQ ID NO:42 :CDR-H3 of the sequence shown in 84; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:129, CDR-L2 containing the sequence shown in SEQ ID NO:170, and CDR-L2 containing the sequence shown in SEQ ID NO:203 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:131, CDR-L2 containing the sequence shown in SEQ ID NO:171, and CDR-L2 containing the sequence shown in SEQ ID NO:204 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:132, CDR-L2 containing the sequence shown in SEQ ID NO:171, and CDR-L2 containing the sequence shown in SEQ ID NO:204 CDR-L3 showing sequence;
- VH heavy chain variable region
- VH Heavy chain variable region containing the following 3 CDRs: CDR-H1 containing the sequence shown in SEQ ID NO:8, CDR-H2 containing the sequence shown in SEQ ID NO:45, and CDR-H2 containing the sequence shown in SEQ ID NO:45 :CDR-H3 of the sequence shown in 87; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:133, CDR-L2 containing the sequence shown in SEQ ID NO:170, and CDR-L2 containing the sequence shown in SEQ ID NO:203 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:136, CDR-L2 containing the sequence shown in SEQ ID NO:171, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:136, CDR-L2 containing the sequence shown in SEQ ID NO:171, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: containing the sequence shown in SEQ ID NO:13 CDR-H1, CDR-H2 comprising the sequence set forth in SEQ ID NO:49, CDR-H3 comprising the sequence set forth in SEQ ID NO:92; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:137, CDR-L2 containing the sequence shown in SEQ ID NO:173, and CDR-L2 containing the sequence shown in SEQ ID NO:208 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:138, CDR-L2 containing the sequence shown in SEQ ID NO:170, and CDR-L2 containing the sequence shown in SEQ ID NO:209 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:139, CDR-L2 containing the sequence shown in SEQ ID NO:170, and CDR-L2 containing the sequence shown in SEQ ID NO:210 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: CDR-H1 containing the sequence shown in SEQ ID NO:15, CDR-H2 containing the sequence shown in SEQ ID NO:53, and CDR-H2 containing the sequence shown in SEQ ID NO:53 :CDR-H3 of the sequence shown in 96; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:124, CDR-L2 containing the sequence shown in SEQ ID NO:164, and CDR-L2 containing the sequence shown in SEQ ID NO:212 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:141, CDR-L2 containing the sequence shown in SEQ ID NO:172, and CDR-L2 containing the sequence shown in SEQ ID NO:213 CDR-L3 showing sequence;
- VH heavy chain variable region
- VH heavy chain variable region
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:143, CDR-L2 containing the sequence shown in SEQ ID NO:177, and CDR-L2 containing the sequence shown in SEQ ID NO:216 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:144, CDR-L2 containing the sequence shown in SEQ ID NO:176, and CDR-L2 containing the sequence shown in SEQ ID NO:215 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:127, CDR-L2 containing the sequence shown in SEQ ID NO:168, and CDR-L2 containing the sequence shown in SEQ ID NO:217 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:144, CDR-L2 containing the sequence shown in SEQ ID NO:169, and CDR-L2 containing the sequence shown in SEQ ID NO:218 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:145, CDR-L2 containing the sequence shown in SEQ ID NO:178, and CDR-L2 containing the sequence shown in SEQ ID NO:219 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:141, CDR-L2 containing the sequence shown in SEQ ID NO:172, and CDR-L2 containing the sequence shown in SEQ ID NO:220 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:146, CDR-L2 containing the sequence shown in SEQ ID NO:180, and CDR-L2 containing the sequence shown in SEQ ID NO:222 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: containing the sequence shown in SEQ ID NO:24 CDR-H1, CDR-H2 comprising the sequence set forth in SEQ ID NO:65, CDR-H3 comprising the sequence set forth in SEQ ID NO:108; and,
- VH heavy chain variable region
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:151, CDR-L2 containing the sequence shown in SEQ ID NO:184, and CDR-L2 containing the sequence shown in SEQ ID NO:227 CDR-L3 showing sequence;
- VH heavy chain variable region
- VH heavy chain variable region
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:156, CDR-L2 containing the sequence shown in SEQ ID NO:189, and CDR-L2 containing the sequence shown in SEQ ID NO:231 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:158, CDR-L2 containing the sequence shown in SEQ ID NO:191, and CDR-L2 containing the sequence shown in SEQ ID NO:233 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:159, CDR-L2 containing the sequence shown in SEQ ID NO:192, and CDR-L2 containing the sequence shown in SEQ ID NO:234 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:160, CDR-L2 containing the sequence shown in SEQ ID NO:193, and CDR-L2 containing the sequence shown in SEQ ID NO:235 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:161, CDR-L2 containing the sequence shown in SEQ ID NO:194, and CDR-L2 containing the sequence shown in SEQ ID NO:236 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:162, CDR-L2 containing the sequence shown in SEQ ID NO:195, and CDR-L2 containing the sequence shown in SEQ ID NO:237 CDR-L3 showing sequence;
- VH Heavy chain variable region containing the following 3 CDRs: containing the sequence shown in SEQ ID NO:37 CDR-H1, CDR-H2 comprising the sequence set forth in SEQ ID NO:79, CDR-H3 comprising the sequence set forth in SEQ ID NO:123; and,
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:163, CDR-L2 containing the sequence shown in SEQ ID NO:196, and CDR-L2 containing the sequence shown in SEQ ID NO:238 CDR-L3 of the sequence shown.
- the CDRs can also be defined according to the Kabat numbering system:
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:395, CDR-L2 containing the sequence shown in SEQ ID NO:396, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:380, CDR-L2 containing the sequence shown in SEQ ID NO:381, and CDR-L2 containing the sequence shown in SEQ ID NO:211 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:365, CDR-L2 containing the sequence shown in SEQ ID NO:366, and CDR-L2 containing the sequence shown in SEQ ID NO:199 CDR-L3 of the sequence shown.
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:395, CDR-L2 containing the sequence shown in SEQ ID NO:396, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH heavy chain variable region
- VH heavy chain variable region
- the CDRs can also be defined according to the Chothia numbering system:
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:395, CDR-L2 containing the sequence shown in SEQ ID NO:396, and CDR-L2 containing the sequence shown in SEQ ID NO:207 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:380, CDR-L2 containing the sequence shown in SEQ ID NO:381, and CDR-L2 containing the sequence shown in SEQ ID NO:211 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:365, CDR-L2 containing the sequence shown in SEQ ID NO:366, and CDR-L2 containing the sequence shown in SEQ ID NO:199 CDR-L3 showing sequence;
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:404, CDR-L2 containing the sequence shown in SEQ ID NO:405, and CDR-L2 containing the sequence shown in SEQ ID NO:406 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:389, CDR-L2 containing the sequence shown in SEQ ID NO:390, and CDR-L2 containing the sequence shown in SEQ ID NO:391 CDR-L3 showing sequence;
- VH heavy chain variable region
- VL light chain variable region containing the following 3 CDRs: CDR-L1 containing the sequence shown in SEQ ID NO:374, CDR-L2 containing the sequence shown in SEQ ID NO:375, and CDR-L2 containing the sequence shown in SEQ ID NO:376 CDR-L3 of the sequence shown.
- the antibodies of the invention or antigen-binding fragments thereof comprise a heavy chain variable region (VH) and a light chain variable region (VL) selected from any of the following groups:
- the antibodies of the invention or antigen-binding fragments thereof are single chain antibodies, such as scFv, di-scFv or (scFv) 2 .
- the antibody or antigen-binding fragment thereof of the invention wherein the antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a humanized antibody or an antibody derived from other species (e.g., rabbit , camel or shark).
- the antibodies of the invention or antigen-binding fragments thereof further comprise a heavy chain constant region (CH) and a light chain constant region (CL).
- CH heavy chain constant region
- CL light chain constant region
- the light chain constant region is selected from the group consisting of kappa or lambda light chain constant regions or variants thereof.
- the antibodies of the invention or antigen-binding fragments thereof comprise a heavy chain constant region and a light chain constant region selected from:
- the heavy chain constant region (CH) of the antibody or antigen-binding fragment thereof of the invention comprises the amino acid sequence shown in SEQ ID NO: 360.
- the light chain constant region is a human IgGl kappa light chain constant region; the light chain constant region (CL) comprises the amino acid set forth in SEQ ID NO: 361.
- the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) as set forth in SEQ ID NO:361 or a variant thereof that is identical to SEQ ID NO:361 than having conservative substitutions of up to 20 amino acids (e.g., conservative substitutions of up to 15, up to 10, or up to 5 amino acids; e.g., conservative substitutions of 1, 2, 3, 4, or 5 amino acids);
- CL light chain constant region
- the antibodies or antigen-binding fragments thereof of the invention are present in less than about 500 nM, such as less than about 100 nM, 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM,
- An EC 50 of 0.3 nM, 0.2 nM, 0.1 nM, 0.01 nM or less binds to tumor cells expressing CDCP1; preferably, the EC 50 is measured by flow cytometry or cell competition ELISA technology.
- the antibody or antigen-binding fragment thereof does not have or has endocytic ability.
- the antibody or antigen-binding fragment thereof does not have the ability to promote tumor cell migration.
- an antibody of the invention or an antigen-binding fragment thereof can be functionally linked (by chemical coupling, genetic fusion, non-covalent linkage, or other means) to one or more other molecular groups, such as another antibody (e.g., forming Bispecific antibodies), detection reagents, pharmaceutical reagents, and/or proteins or polypeptides capable of mediating the binding of an antibody or antigen-binding fragment to another molecule (e.g., avidin or polyhistidine tags).
- another antibody e.g., forming Bispecific antibodies
- detection reagents e.g., pharmaceutical reagents, and/or proteins or polypeptides capable of mediating the binding of an antibody or antigen-binding fragment to another molecule (e.g., avidin or polyhistidine tags).
- bispecific antibody is produced by cross-linking 2 or more antibodies (of the same type or of different types).
- Methods for obtaining bispecific antibodies are well known in the art, and examples thereof include, but are not limited to, chemical cross-linking methods, cell engineering methods (hybridoma methods) or genetic engineering methods.
- the therapeutic moiety of the present invention may be a bacterial toxin, a cytotoxic drug or a radioactive toxin, examples of which include, but are not limited to, taxol, cytochalasin B, mitomycin, Etoposide, vincristine or other antimetabolites, alkylating agents, antibiotics or antimitotic drugs.
- thermometric markers such as colloidal gold or colored glass or plastic (e.g., poly styrene, polypropylene, latex, etc.), and biotin for binding to avidin modified with the above label (e.g., streptavidin).
- Patents teaching the use of this marker include, but are not limited to, U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all incorporated herein by reference). Detectable labels as described above can be detected by methods known in the art.
- radioactive labels can be detected using photographic film or a scintillation calculator, and fluorescent labels can be detected using a light detector to detect the emitted light.
- Enzyme markers are generally detected by providing a substrate to the enzyme and detecting the reaction product produced by the enzyme's action on the substrate, and thermometric markers are detected by simply visualizing a colored marker.
- such labels can be adapted for immunological detection (eg, enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescence immunoassay, etc.).
- detectable labels as described above can be linked to the antibodies or antigen-binding fragments thereof of the invention via linkers of varying lengths to reduce potential steric hindrance.
- the antibodies of the invention or antigen-binding fragments thereof can also be derivatized with chemical groups, such as polyethylene glycol (PEG), methyl or ethyl groups, or sugar groups. These groups can be used to improve the biological properties of the antibody, such as increasing serum half-life.
- chemical groups such as polyethylene glycol (PEG), methyl or ethyl groups, or sugar groups. These groups can be used to improve the biological properties of the antibody, such as increasing serum half-life.
- the structure of the conjugate is as shown in formula (I):
- A is the antibody of the present invention or its antigen-binding fragment, or the multispecific antibody of the present invention
- L is a linker.
- the linker is a vc linker, and its structure is:
- the coupling moiety is a toxin, which includes a cytotoxic agent; more preferably, the cytotoxic agent is selected from the group consisting of camptothecins (e.g., SN-38), maytansinoids ( For example, maytansine DM1/4), pyrrolobenzodiazepines (PBDs) or auristatins (such as Monomethyl auristatin E/F).
- camptothecins e.g., SN-38
- maytansinoids For example, maytansine DM1/4
- PPDs pyrrolobenzodiazepines
- auristatins such as Monomethyl auristatin E/F
- the value of p is greater than or equal to 0;
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising an antibody of the invention or an antigen-binding fragment thereof or a prodrug (eg probody), a conjugate, a multispecific antibody, and a pharmaceutically acceptable carriers and/or excipients.
- the antibody or antigen-binding fragment thereof and the additional pharmaceutically active agent are provided as separate components or as components of the same composition.
- the disease associated with CDCP1 is a tumor.
- the antibodies or antigen-binding fragments, conjugates, multispecific antibodies or pharmaceutical compositions thereof of the invention are administered separately, in combination, simultaneously or sequentially with another pharmaceutically active agent.
- the additional pharmaceutically active agent is a drug with anti-tumor activity, such as platinum-based drugs, small molecule inhibitors, etc.
- the additional pharmaceutically active agent is an immunity-enhancing drug, such as interferon, interleukin.
- the additional pharmaceutically active agent is an immune checkpoint inhibitor (e.g., a PD-1, PD-L1, or CTLA-4 inhibitor);
- an immune checkpoint inhibitor e.g., a PD-1, PD-L1, or CTLA-4 inhibitor
- the additional pharmaceutically active agent is an oncolytic virus, immune cell, or engineered immune cell.
- the invention provides a method for preventing and/or treating and/or adjuvant treatment and/or neoadjuvant treatment of a disease associated with CDCP1 in a subject, said method comprising administering to a patient in need thereof A subject is administered an effective amount of an antibody or an antigen-binding fragment thereof, a conjugate, a multispecific antibody or a pharmaceutical composition thereof of the invention.
- the disease associated with CDCP1 is a tumor.
- the tumor is selected from solid tumors or hematological tumors.
- the solid tumor is selected from the group consisting of esophageal cancer, gastrointestinal cancer, pancreatic cancer, thyroid cancer, colorectal cancer, renal cancer, lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, or small cell lung cancer) , liver cancer, stomach cancer, gastroesophageal junction (GEJ) adenocarcinoma, head and neck cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, germ cell cancer, bone cancer, skin cancer, thymus carcinoma, cholangiocarcinoma, gallbladder cancer, melanoma, mesothelioma, sarcoma or glioblastoma; the hematological tumor is selected from lymphoma, myeloma (eg multiple myeloma) or leukemia.
- lung cancer e.g., lung adenocarcinoma, lung squam
- the invention provides a method for detecting the presence of CDCP1 or its level in a sample, which comprises allowing the antibody or antigen-binding fragment thereof, multispecific antibody, conjugate or pharmaceutical composition of the invention to be combined with CDCP1 contacting the sample with the antibody or antigen-binding fragment thereof, multispecific antibody, conjugate or pharmaceutical composition under conditions that form a complex therebetween, and detecting the formation of the complex.
- the invention provides an antibody of the invention or an antigen-binding fragment, conjugate, multispecific thereof for use in the prevention and/or treatment and/or adjuvant treatment and/or neoadjuvant treatment of diseases associated with CDCP1 Antibodies or pharmaceutical compositions.
- the disease associated with CDCP1 is a tumor.
- the tumor is selected from solid tumors or hematological tumors.
- the solid tumor is selected from the group consisting of esophageal cancer, gastrointestinal cancer, pancreatic cancer, thyroid cancer, colorectal cancer, renal cancer, lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, or small cell lung cancer) , liver cancer, stomach cancer, gastroesophageal junction (GEJ) adenocarcinoma, head and neck cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, Germ cell cancer, bone cancer, skin cancer, thymus cancer, cholangiocarcinoma, gallbladder cancer, melanoma, mesothelioma, sarcoma or glioblastoma; the blood tumor is selected from lymphoma, myeloma (such as multiple myeloma) or leukemia.
- lung cancer e.g., lung adenocarcinoma, lung squamous cell
- the invention provides an antibody or an antigen-binding fragment, conjugate, multispecific antibody or pharmaceutical composition thereof of the invention for use in the diagnosis or differential diagnosis of a disease associated with CDCP1.
- the disease associated with CDCP1 is a tumor.
- the tumor is selected from solid tumors or hematological tumors.
- the solid tumor is selected from the group consisting of esophageal cancer, gastrointestinal cancer, pancreatic cancer, thyroid cancer, colorectal cancer, renal cancer, lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, or small cell lung cancer) , liver cancer, stomach cancer, gastroesophageal junction (GEJ) adenocarcinoma, head and neck cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, germ cell cancer, bone cancer, skin cancer, thymus carcinoma, cholangiocarcinoma, gallbladder cancer, melanoma, mesothelioma, sarcoma or glioblastoma; the hematological tumor is selected from lymphoma, myeloma (eg multiple myeloma) or leukemia.
- lung cancer e.g., lung adenocarcinoma, lung squam
- the antibody or antigen-binding fragment thereof, the pharmaceutical composition of the invention or the immunogenic composition of the invention can be formulated into any dosage form known in the medical field, for example, tablets, pills, suspensions, emulsions, solutions , gels, capsules, powders, granules, elixirs, tablets, suppositories, injections (including injections, sterile powders for injection and concentrated solutions for injection), inhalants, sprays, etc.
- the preferred dosage form depends on the intended mode of administration and therapeutic use.
- the pharmaceutical compositions of the present invention should be sterile and stable under the conditions of production and storage.
- One preferred dosage form is an injection. Such injections may be sterile injectable solutions.
- sterile injectable solutions may be prepared by incorporating the requisite dosage of a recombinant protein of the invention in an appropriate solvent, optionally with other desired ingredients (including, but not limited to, pH adjustment). agent, surfactant, adjuvant, ionic strength enhancer, isotonic agent, preservative, diluent, or any combination thereof) followed by filter sterilization.
- sterile injectable solutions may be prepared as sterile lyophilized powders (for example, by vacuum drying or freeze drying) for ease of storage and use. Such sterile lyophilized powders can be dispersed in a suitable carrier, such as sterile pyrogen-free water, before use.
- antibodies of the invention or antigen-binding fragments thereof may be present in pharmaceutical or immunogenic compositions in unit dosage form to facilitate administration.
- the antibodies or antigen-binding fragments thereof, pharmaceutical compositions or immunogenic compositions of the invention may be administered by any suitable method known in the art, including, but not limited to, oral, buccal, sublingual, ophthalmic, topical, enteral Externally, rectum, intraleaf sheath, intracytoplasmic reticulum, inguinal, intravesical, topical (eg, powder, ointment, or drops), or nasal route.
- the preferred route/mode of administration is parenteral (eg intravenous, subcutaneous, intraperitoneal, intramuscular). The skilled artisan will understand that the route and/or mode of administration will vary depending on the intended purpose.
- the antibody or antigen-binding fragment thereof, pharmaceutical composition or immunogenic composition of the invention is administered by intravenous infusion or injection.
- the pharmaceutical composition or immunogenic composition of the present invention may include an "effective amount”("therapeutically effective amount” or “prophylactically effective amount”). “Amount”) of the antibody or antigen-binding fragment thereof of the invention.
- a “prophylactically effective amount” refers to an amount sufficient to prevent, prevent, or delay the occurrence of a disease.
- a “therapeutically effective amount” refers to an amount sufficient to cure or at least partially prevent a disease. The amount of disease and its complications in a patient suffering from the disease.
- the therapeutically effective amount of an antibody or antigen-binding fragment thereof of the invention may vary depending on factors such as: the severity of the disease to be treated, the overall state of the patient's own immune system , the patient's general conditions such as age, weight and gender, the way the drug is administered, and other treatments administered at the same time, etc.
- the dosing regimen can be adjusted to obtain the optimal desired response (eg, therapeutic or prophylactic response).
- the dose may be administered as a single dose, may be administered multiple times over a period of time, or may be proportionally reduced or increased according to the exigencies of the treatment situation.
- dosage may vary depending on the type and severity of symptoms requiring treatment.
- those skilled in the art understand that for any particular patient, the specific dosage regimen should be adjusted over time based on the needs of the patient and the professional evaluation of the physician; the dosage ranges given here are for illustrative purposes only and are not limiting. Use or scope of pharmaceutical compositions or immunogenic compositions of the invention.
- the invention provides containers (eg plastic or glass vials, eg with caps or chromatography columns, hollow bore needles or syringe barrels) containing any of the antibodies or antigen-binding fragments of the invention, or pharmaceutical compositions.
- containers eg plastic or glass vials, eg with caps or chromatography columns, hollow bore needles or syringe barrels
- the invention also provides an injection device comprising any of the antibodies or antigen-binding fragments, or pharmaceutical compositions of the invention.
- the antibody or antigen-binding fragment thereof of the present invention can specifically bind CDCP1 and thus can be used to detect the presence or level of CDCP1 in a sample.
- the invention provides a kit comprising an antibody or antigen-binding fragment thereof, multispecific antibody, conjugate or pharmaceutical composition of the invention.
- the antibodies of the invention, or antigen-binding fragments thereof are detectably labeled.
- the kit further includes a second antibody that specifically recognizes the antibody of the invention or its antigen-binding fragment.
- the second antibody further includes a detectable label.
- the detectable label may be any substance detectable by fluorescent, spectroscopic, photochemical, biochemical, immunological, electrical, optical or chemical means. It is particularly preferred that such labels can be adapted to immunological detection (eg, enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescence immunoassay, etc.).
- immunological detection eg, enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescence immunoassay, etc.
- radioactive labels can be detected using photographic film or a scintillation calculator, and fluorescent labels can be detected using a light detector to detect the emitted light.
- Enzyme markers are generally detected by providing a substrate to the enzyme and detecting the reaction product produced by the enzyme's action on the substrate, and thermometric markers are detected by simply visualizing a colored marker.
- detectable labels as described above can be linked to recombinant proteins of the invention via linkers of varying lengths to reduce potential steric hindrance.
- the invention provides the use of the antibody or antigen-binding fragment, conjugate, multispecific antibody or pharmaceutical composition thereof of the invention in the preparation of a diagnostic kit for diagnosis or identification. Diagnosing CDCP1-related diseases.
- the disease associated with CDCP1 is a tumor.
- the tumor is selected from solid tumors or hematological tumors
- antibody refers to an immunoglobulin molecule typically composed of two pairs of polypeptide chains, each pair having a light chain (LC) and a heavy chain (HC).
- Antibody light chains can be classified into kappa (kappa) and lambda (lambda) light chains.
- Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
- the variable and constant regions pass through a "J" of approximately 12 or more amino acids regions, the heavy chain also contains a "D" region of approximately 3 or more amino acids.
- Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
- the heavy chain constant region of IgG consists of 3 domains (CH1, CH2, and CH3).
- Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
- the light chain constant region consists of one domain, CL.
- the constant domain is not directly involved in the binding of antibodies to antigens, but exhibits a variety of effector functions, such as mediating the interaction of immunoglobulins with host tissues or factors, including various cells of the immune system (e.g., effector cells) and classical complement. Binding of the first component of the system (C1q).
- VH and VL regions can also be subdivided into regions of high variability called complementarity determining regions (CDRs), interspersed with more conservative regions called framework regions (FRs).
- CDRs complementarity determining regions
- FRs framework regions
- Each VH and VL consists of 3 CDRs and 4 FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions (VH and VL) of each heavy chain and light chain pair respectively form an antigen-binding site.
- the assignment of amino acids to each region or domain can follow Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk (1987) J. Mol. Biol. 196:901- 917; Definition of Chothia et al. (1989) Nature 342:878-883.
- antibody includes not only intact antibodies but also antigen-binding fragments of the antibodies, unless the context clearly indicates otherwise.
- CDR complementarity determining region
- the variable regions of the heavy chain and light chain each contain three CDRs, named CDR1, CDR2 and CDR3.
- CDR1, CDR2 and CDR3 The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda , Md., 1991), Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al.
- the CDRs contained in the antibodies of the present invention or antigen-binding fragments thereof can be determined according to various numbering systems known in the art, such as Kabat, Chothia, IMGT, AbM or Contact numbering systems.
- the antibodies of the invention, or antigen-binding fragments thereof contain CDRs determined by the Kabat, Chothia, IMGT, AbM, or Contact numbering system.
- framework region or "FR” residues refers to those amino acid residues in an antibody variable region other than the CDR residues as defined above.
- antibody is not limited to any particular method of producing the antibody. This includes, for example, recombinant antibodies, monoclonal antibodies, and polyclonal antibodies.
- the antibodies may be of different isotypes, for example, IgG (eg, IgGl, IgG2, IgG3 or IgG4 subtypes), IgA1, IgA2, IgD, IgE or IgM antibodies.
- antigen-binding fragment of an antibody refers to a polypeptide comprising a fragment of a full-length antibody that retains the ability to specifically bind to the same antigen that the full-length antibody binds, and/or competes with the full-length antibody Specific binding to an antigen, which is also called an "antigen-binding moiety.”
- an antigen-binding moiety which is also called an "antigen-binding moiety.”
- Non-limiting examples of antigen-binding fragments include Fab, Fab', F(ab') 2 , Fd, Fv, complementarity determining region (CDR) fragments, scFv, diabody, single domain antibody, chimeric antibody, linear antibody, nanobody (technology from Domantis), probody and such polypeptides, which contain sufficient antigen to confer specificity to the polypeptide At least a portion of the antibody with binding capacity.
- full-length antibody means an antibody consisting of two “full-length heavy chains” and two “full-length light chains.”
- “full-length heavy chain” refers to a polypeptide chain that consists of a heavy chain variable region (VH), a heavy chain constant region CH1 domain, a hinge region (HR), and a heavy chain in the direction from the N end to the C end. It consists of a constant region CH2 domain and a heavy chain constant region CH3 domain; and, when the full-length antibody is of IgE isotype, optionally also includes a heavy chain constant region CH4 domain.
- a "full-length heavy chain” is a polypeptide chain consisting of VH, CH1, HR, CH2 and CH3 in the N-terminal to C-terminal direction.
- a "full-length light chain” is a polypeptide chain consisting of a light chain variable region (VL) and a light chain constant region (CL) in the N-terminal to C-terminal direction.
- VL light chain variable region
- CL light chain constant region
- the two pairs of full-length antibody chains are linked together by disulfide bonds between CL and CH1 and between the HRs of the two full-length heavy chains.
- Full-length antibodies contain two antigen-binding sites formed by VH and VL pairs respectively, and these two antigen-binding sites specifically recognize/bind the same antigen.
- Fab fragment means an antibody fragment consisting of the VL, VH, CL and CH1 domains
- F(ab') 2 fragment means an antibody fragment consisting of a fragment that passes through a disulfide bridge on the hinge region An antibody fragment that connects two Fab fragments
- Fab'fragment means the fragment obtained by reducing the disulfide bond connecting the two heavy chain fragments in the F(ab') 2 fragment, consisting of a complete light chain and heavy chain. The Fd fragment of the chain (consisting of VH and CH1 domains).
- Fv means an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. Fv fragments are generally considered to be the smallest antibody fragments that can form a complete antigen-binding site. It is generally believed that six CDRs confer the antigen-binding specificity of an antibody. However, even a variable region (such as the Fd fragment) Containing only three CDRs specific for the antigen) can also recognize and bind the antigen, although the affinity may be lower than that of the complete binding site.
- the term "Fc domain” or "Fc region” means a portion of the heavy chain constant region that includes CH2 and CH3.
- the Fc fragment of an antibody has many different functions but does not participate in antigen binding.
- "Effector functions" mediated by the Fc region include Fc receptor binding; Clq binding and complement-dependent cytotoxicity (CDC); antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; effects on cell surface receptors Down-regulation of receptors (e.g., B-cell receptors); and B-cell activation, etc.
- the Fc region includes hinge, CH2, and CH3. When the Fc region includes a hinge, the hinge mediates dimerization between the two Fc-containing polypeptides.
- the Fc region can be of any antibody heavy chain constant region isotype, such as IgGl, IgG2, IgG3 or IgG4.
- the Fc domain may include either a native Fc region or a variant Fc region.
- Native Fc regions include amino acid sequences that are consistent with the amino acid sequences of Fc regions found in nature, for example, native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human Fc regions IgG3 Fc region; and native sequence human IgG4 Fc region, and naturally occurring variants thereof.
- a variant Fc region includes an amino acid sequence that differs from the amino acid sequence of a native sequence Fc region due to at least one amino acid modification.
- a variant Fc region may possess altered effector functions (e.g., Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function) compared to the native Fc region. .
- scFv refers to a single polypeptide chain comprising VL and VH domains connected by a linker.
- Such scFv molecules may have the general structure: NH2 -VL-linker-VH-COOH or NH2 -VH-linker-VL-COOH.
- Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof.
- GGGGS linker with the amino acid sequence
- a disulfide bond may also exist between VH and VL of scFv.
- the term "diabody” means one whose VH and VL domains are expressed on a single polypeptide chain but using a linker that is too short to allow pairing between the two domains of the same chain, This forces the domain to pair with the complementary domain of the other chain and creates two antigen binding sites (see, e.g., Holliger P. et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993), and Poljak R.J. et al., Structure 2:1121-1123 (1994)).
- Each of the above antibody fragments retains the ability to specifically bind to the same antigen that the full-length antibody binds, and/or competes with the full-length antibody for specific binding to the antigen.
- bispecific antibody refers to a conjugate (conjugate) formed by a first antibody (fragment) and a second antibody (fragment) or antibody analog through a coupling arm. Methods of linkage include but are not limited to chemical reactions, gene fusion, protein fusion, polypeptide fusion and enzymatic fusion.
- Multispecific antibodies include, for example: trispecific antibodies and tetraspecific antibodies, where the former are antibodies with three different antigen-binding specificities, while the latter are antibodies with four different antigen-binding specificities.
- techniques for obtaining antibodies may use conventional techniques known to those skilled in the art (e.g., recombinant DNA technology or enzymatic or chemical fragmentation methods) to obtain the antigen of the antibody from a given antibody (e.g., the antibodies provided by the invention). Binding fragments (eg, the antibody fragments described above), and the antigen-binding fragments of the antibodies are screened for specificity in the same manner as for intact antibodies.
- the terms “monoclonal antibody”, “monoclonal antibody” and “mAb” have the same meaning and are used interchangeably and refer to one from a group of highly homologous antibody molecules.
- An antibody or a fragment of an antibody that is, a group of identical antibody molecules except for natural mutations that may occur spontaneously.
- Monoclonal antibodies are highly specific for a single epitope on the antigen.
- Polyclonal antibodies are relative to monoclonal antibodies, which usually contain at least two or more different antibodies, and these different antibodies usually recognize different epitopes on the antigen.
- the modifier "monoclonal” merely indicates that the antibody is characterized as being obtained from a highly homologous population of antibodies and is not construed as requiring any specific method to prepare the antibody.
- murine antibody refers to the fusion of B cells derived from immunized mice with myeloma cells and the subsequent selection of murine hybrid fusion cells that can proliferate indefinitely and secrete antibodies. Then proceed to screening, antibody preparation and antibody purification. Or B cells differentiate and proliferate after the antigen invades the mouse body to form plasma cells, which can produce and secrete antibodies. Stimulated by specific antigens, antibodies are produced because the antigen invades the human body and causes the interaction of various immune cells, causing B cells in lymphocytes to differentiate and proliferate to form plasma cells. Plasma cells can produce and secrete antibodies.
- humanized antibody refers to a non-human antibody that has been genetically engineered and whose amino acid sequence has been modified to increase sequence homology to that of a human antibody.
- CDR region of a humanized antibody comes from a non-human antibody (donor antibody), and all or part of the non-CDR region (for example, variable region FR and or or constant region) comes from a human source.
- Humanized antibodies usually retain the expected properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance immune response, etc.
- the donor antibody may be a mouse, rat, rabbit, or non-human primate with desired properties (e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance immune responses).
- desired properties e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance immune responses.
- Humanized antibodies can not only retain the expected properties of non-human donor antibodies (such as mouse antibodies), but also effectively reduce the immunogenicity of non-human donor antibodies (such as mouse antibodies) in human subjects, Therefore, it is particularly advantageous.
- the expected properties of the humanized antibody e.g., antigen specificity, affinity, reactivity, ability to enhance immune cell activity, and/or The ability to enhance an immune response
- non-human donor antibodies e.g., murine antibodies
- a high degree of humanization for example, at least 75%, at least 80%, at least 85%, at least 90%, At least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% humanized
- the humanized antibody in order for the humanized antibody to retain the properties of the donor antibody as much as possible (including, for example, antigen specificity, affinity, reactivity, the ability to increase immune cell activity, and/or the ability to enhance immune response), the humanized antibody is
- the framework region (FR) of the humanized antibody of the invention may contain both the amino acid residues of the human acceptor antibody and the corresponding amino acid residues of the non-human donor antibody.
- degree of humanization is a metric used to evaluate the number of non-human amino acid residues in a humanized antibody.
- the degree of humanization of a humanized antibody can be predicted by using the IMGT website DomainGapAlign to predict the homology between the variable region sequence and the human V domain.
- the term "specific binding” refers to a non-random binding reaction between two molecules, such as the reaction between an antibody and the antigen against which it is directed.
- the strength or affinity of a specific binding interaction can be expressed as the equilibrium dissociation constant (KD) or half-maximal effect concentration ( EC50 ) of the interaction.
- the specific binding properties between two molecules can be determined using methods known in the art.
- One approach involves measuring the rate at which antigen binding sites or antigen complexes form and dissociate.
- Both the "association rate constant” (ka or kon) and the “dissociation rate constant” (kdis or koff) can be calculated from the concentration and the actual rates of association and dissociation (see Malmqvist M, Nature, 1993, 361 :186-187).
- the ratio of kdis or kon is equal to the dissociation constant KD (see Davies et al., Annual Rev Biochem, 1990;59:439-473).
- KD, kon and kdis values can be measured by any valid method.
- the dissociation constant can be measured using bioluminescence interferometry (e.g., ForteBio Octet method).
- bioluminescence interferometry e.g., ForteBio Octet method
- surface plasmon resonance techniques e.g Biacore
- Kinexa can be used to measure dissociation constants.
- the term "vector” refers to a nucleic acid delivery vehicle into which a polynucleotide can be inserted.
- the vector can express the protein encoded by the inserted polynucleotide, the vector is called an expression vector.
- the vector can be introduced into the host cell through transformation, transduction or transfection, so that the genetic material elements it carries can be expressed in the host cell.
- Vectors are well known to those skilled in the art, including but not limited to: plasmids; phagemids; Cos plasmid; artificial chromosome, such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or P1-derived artificial chromosome (PAC); phage such as lambda phage or M13 phage and animal viruses, etc.
- artificial chromosome such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or P1-derived artificial chromosome (PAC)
- phage such as lambda phage or M13 phage and animal viruses, etc.
- Animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (such as herpes simplex virus), poxviruses, baculoviruses, papillomaviruses, papillomaviruses, Polyomavacuolating viruses (such as SV40).
- retroviruses including lentiviruses
- adenoviruses such as herpes simplex virus
- poxviruses poxviruses
- baculoviruses papillomaviruses
- papillomaviruses papillomaviruses
- Polyomavacuolating viruses such as SV40.
- a vector can contain a variety of expression-controlling elements, including, but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes
- the term "host cell” refers to a cell that can be used to introduce a vector, which includes, but is not limited to, prokaryotic cells such as E. coli or Bacillus subtilis, fungal cells such as yeast cells or Aspergillus, etc. Insect cells such as S2 Drosophila cells or Sf9, or animal cells such as fibroblasts, CHO cells, COS cells, NSO cells, HeLa cells, BHK cells, HEK 293 cells or human cells.
- identity is used to refer to the match of sequences between two polypeptides or between two nucleic acids.
- the sequences are aligned for optimal comparison purposes (e.g., gaps may be introduced in the first amino acid sequence or nucleic acid sequence to best match the second amino acid or nucleic acid sequence). Good comparison).
- the amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. Molecules are identical when a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence.
- Determination of percent identity between two sequences can also be accomplished using mathematical algorithms.
- One non-limiting example of a mathematical algorithm for comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Improved in .Acad.Sci.U.S.A.90:5873-5877.
- Such algorithms were integrated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403.
- variant in the context of polypeptides (including polypeptides), also refers to a polypeptide or peptide comprising an amino acid sequence that has been altered by introducing substitutions, deletions, or additions of amino acid residues. In some cases, the term “variant” also refers to a polypeptide or peptide that has been modified (ie, by covalently linking any type of molecule to the polypeptide or peptide).
- polypeptides may be modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protective blocking groups, proteolytic cleavage, ligation to cell ligands or other proteins, etc.
- Derivatized polypeptides or peptides can be produced by chemical modification using techniques known to those skilled in the art, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like.
- a variant has a similar, identical or improved function to the polypeptide or peptide from which it is derived.
- conservative substitution means one that does not adversely affect or alter the amino acid sequence comprising Amino acid substitutions for expected properties of proteins and polypeptides.
- conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
- Conservative amino acid substitutions include those in which an amino acid residue is replaced with an amino acid residue having a similar side chain, e.g., one that is physically or functionally similar to the corresponding amino acid residue (e.g., has similar size, shape, charge, chemical properties, including ability to form covalent bonds or hydrogen bonds, etc.). Families of amino acid residues with similar side chains have been defined in the art.
- These families include those with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine , asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (such as alanine, valine, leucine, isoleucine amino acids, proline, phenylalanine, methionine), ⁇ -branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, Phenylalanine, tryptophan, histidine) amino acids.
- basic side chains e.g., lysine, arginine, and histidine
- acidic side chains e.g., aspartic acid, glutamic acid
- amino acid residues can be divided into categories defined by optional physical and functional properties. For example, alcohol-containing residues (S and T), aliphatic residues (I, L, V, and M), cycloalkenyl-related residues (F, H, W, and Y), hydrophobic residues (A, C, F, G, H, I, L, M, R, T, V, W and Y), negatively charged residues (D and E), polar residues (C, D, E, H, K , N, Q, R, S and T), positively charged residues (H, K and R), small residues (A, C, D, G, N, P, S, T and V), polar Small residues (A, G and S), residues involved in turn formation (A, C, D, E, G, H, K, N, Q, R, S, P and T), flexible residues (Q , T, K, S,
- amino acids involved in this article have been prepared following conventional usage. See, e.g., Immunology-A Synthesis (2nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.
- polypeptide and “protein” have the same meaning and are used interchangeably.
- amino acids are generally represented by one-letter and three-letter abbreviations well known in the art. For example, alanine can be represented by A or Ala.
- linker refers to the molecular moiety used to connect an antibody targeting a specific antigen, or an antigen-binding fragment thereof, to a coupling moiety to form a conjugate. In some cases, the linker also includes a spacer to modify the steric hindrance of the coupling moiety. In some conjugates, the linker is required; in other conjugates, the linker is not required. The linkers are divided into non-cleavable linkers and cleavable linkers.
- Conjugates containing the non-cleavable linker require internalization to degrade the antibody or antigen-binding fragment thereof to release the conjugated moiety; conjugates containing the cleavable linker may degrade the antibody or antigen-binding fragment thereof via internalization fragment to release the conjugated moiety, or may be destroyed not by internalization but by enzymatic or chemical catalytic cleavage occurring at the cleavage site
- the linker is structured to release the coupling moiety.
- non-cleavable linkers include N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).
- cleavable linker examples include linkers using disulfide bonds as cleavage sites, hydrazone linkers using acyl groups as cleavage sites, linkers using enzyme catalytic sites as cleavage sites (such as dipeptide linkers Val-Cit, Val-Ala; tetrapeptide linker Gly-Gly-Phe-Gly; linker containing phosphate and pyrophosphate).
- the linker can be covalently connected to the antibody or antigen-binding fragment thereof and the coupling moiety through reaction of chemical functional groups through coupling techniques known in the art.
- the coupling technology can be specific in-situ antibody modification based on chemistry, such as using lysine residues to react with electrophilic groups to achieve connection, using disulfide bond reactions to achieve connection, using sulfhydryl groups to perform re-bridging to achieve connection, Ligation is achieved using glycan glycosylation.
- the coupling technology can also be site-specific bioconjugation based on engineered antibodies. For example, natural amino acids or non-natural amino acids specifically recognized by enzymes are added to the antibodies to realize the connection through enzyme catalysis.
- the term "pharmaceutically acceptable carrier and/or excipient” means a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, They are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers Agents, diluents, agents to maintain osmotic pressure, agents to delay absorption, preservatives.
- pH adjusting agents include, but are not limited to, phosphate buffer.
- Surfactants include, but are not limited to, cationic, anionic or nonionic surfactants such as Tween-80.
- Ionic strength enhancers include, but are not limited to, sodium chloride.
- Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc.
- Agents that maintain osmotic pressure include, but are not limited to, sugar, NaCl, and the like.
- Agents that delay absorption include, but are not limited to, monostearate and gelatin.
- Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like.
- Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc.
- Stabilizers have the meaning commonly understood by those skilled in the art, which can stabilize the desired activity of active ingredients in medicines, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose) , lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dry whey, albumin or casein) or their degradation products (such as lactalbumin hydrolyzate), etc.
- sugars such as sorbitol, mannitol, starch, sucrose
- lactose lactose
- dextran or glucose
- amino acids such as glutamic acid, glycine
- proteins such as dry whey, albumin or casein
- degradation products such as lactalbumin hydrolyzate
- prevention refers to a method performed to prevent or delay the occurrence of a disease or condition or symptom in a subject.
- treatment refers to a method performed to obtain a beneficial or desired clinical result.
- beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction of the extent of the disease, stabilization (i.e., no worsening) of the state of the disease, delaying or slowing the progression of the disease, ameliorating or alleviating the disease. status, reducing or inhibiting the recurrence of disease and relieving symptoms (regardless of partial or all), whether detectable or undetectable.
- treatment may also refer to prolonging survival compared to expected survival if not receiving treatment.
- the term "subject” refers to a mammal, such as a primate mammal, such as a human.
- the subject eg, a human
- has, or is at risk for, a tumor eg, an MSLN-expressing tumor
- an inflammatory disease e.g, an autoimmune disease.
- an effective amount refers to an amount sufficient to obtain, at least in part, the desired effect.
- an effective amount for preventing disease e.g., tumors, inflammatory diseases, or autoimmune diseases
- an effective amount for preventing disease refers to an amount sufficient to prevent, prevent, or delay the occurrence of the disease (e.g., tumors, inflammatory diseases, or autoimmune diseases); treating a disease
- An effective amount is an amount sufficient to cure or at least partially prevent disease and its complications in a patient already suffering from the disease. Determining such effective amounts is well within the capabilities of those skilled in the art.
- the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall status of the patient's own immune system, the patient's general condition such as age, weight and gender, the manner in which the drug is administered, and other treatments administered concurrently etc.
- cancer and “tumor” are used interchangeably and refer to a large group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division may lead to the formation of malignant tumors or cells that invade adjacent tissues and may metastasize to distant parts of the body via the lymphatic system or bloodstream. Cancer includes benign and malignant cancers as well as dormant tumors or micrometastases. Cancer also includes hematological malignancies.
- the term "pharmaceutically acceptable” means that the molecule itself, molecule fragments or compositions do not produce adverse, allergic or other adverse reactions when properly administered to animals or humans.
- Specific examples of substances that can serve as pharmaceutically acceptable carriers or components thereof include sugars (such as lactose), starch, cellulose and its derivatives, vegetable oils, gelatin, polyols (such as propylene glycol), alginic acid, etc.
- combination therapy includes combining an anti-CDCPl antibody, or antigen-binding fragment thereof, contemplated by the invention with one or more additional active therapeutic agents (eg, chemotherapeutic agents) of a second therapy or other prophylactic or therapeutic modalities (eg, radiation therapy) Use in combination.
- additional active therapeutic agents eg, chemotherapeutic agents
- a second therapy or other prophylactic or therapeutic modalities eg, radiation therapy
- anti-cancer agents may include chemotherapeutic agents (e.g., mitotic inhibitors), alkylating agents (e.g., Nitrogen Mustard), antimetabolites (e.g., folic acid analogs), natural products (e.g., vinca alkaloids) Vinca Alkaloid), various reagents (such as platinum coordination complexes), hormones and antagonists (such as adrenocortical steroids), immunomodulators (such as Bropirimine, Upjohn), etc.
- chemotherapeutic agents e.g., mitotic inhibitors
- alkylating agents e.g., Nitrogen Mustard
- antimetabolites e.g., folic acid analogs
- natural products e.g., vinca alkaloids
- Vinca Alkaloid e.g., vinca alkaloids
- various reagents such as platinum coordination complexes
- hormones and antagonists such as adrenocortical steroids
- immunomodulators such as Bropirimine, Up
- Combination therapies include therapeutic agents that affect the immune response (eg, enhance or activate the response) and therapeutic agents that affect (eg, inhibit or kill) tumors or cancer cells. Combination therapy reduces the likelihood of drug-resistant cancer cells developing. Combination therapy may allow for dosage reduction of one or more of the agents to reduce or eliminate interaction with one or more of the agents. related adverse effects.
- Such combination therapies may have a synergistic therapeutic or preventive effect on the underlying disease, disorder or condition.
- “combination” includes therapies that may be administered separately, for example, formulated separately for separate administration (eg, may be provided in a kit), as well as therapies that may be administered together in a single formulation (i.e., a "co-formulation") .
- the anti-CDCP1 antibodies or antigen-binding fragments thereof of the invention can be administered sequentially.
- anti-CDCP1 antibodies or antigen-binding fragments thereof can be administered simultaneously.
- the anti-CDCP1 antibodies or antigen-binding fragments thereof of the invention may be used in any combination with at least one other (active) agent.
- the anti-CDCP1 antibodies provided by the present invention have obvious advantages, such as better target binding ability, tumor cell binding ability, endocytosis ability, and better inhibition of tumor cell migration. ability, with better medicinal properties.
- the invention also provides anti-CDCP1 antibody conjugates that can target CDCP1-positive cells.
- the antibody conjugate of the present invention can target CDCP1-positive cells with high affinity and specificity, which is very beneficial for treating cancer or in vivo diagnosis.
- the examples also prove that the ADC of the present invention has strong killing activity against various tumor cell lines expressing human CDCP1, such as colorectal cancer, breast cancer, and prostate cancer. Furthermore, in the mouse colorectal cancer xenograft tumor model, the ADC of the present invention showed significant tumor inhibitory activity and had good safety.
- Figure 1 Schematic structural diagram of CDCP1-C, CDCP1-A, and CDCP1-B;
- Figure 3 Laser confocal detection results of antibody internalization in tumor cell lines; green in the figure indicates anti-CDCP1 antibodies, red indicates lysosome, and arrows indicate their co-localization in cells after endocytosis;
- FIG. 4a Effect of anti-CDCP1 antibody on the proliferation of MDA-MB-231 tumor cells
- Figure 4b Effect of anti-CDCP1 antibody on the proliferation of PC3 tumor cells
- Figure 4c Effect of anti-CDCP1 antibody on the migration ability of tumor cells
- Figure 5 Inhibitory effect of anti-CDCP1 chimeric antibody-vcMMAE conjugate on tumor cell growth
- Figure 6a Inhibitory effect of anti-CDCP1 humanized antibody-vcMMAE conjugate on the growth of HCC1806 tumor cells
- Figure 6b Inhibitory effect of anti-CDCP1 humanized antibody-vcMMAE conjugate on the growth of HCT116 tumor cells
- Figure 7a Detection of the effect of anti-CDCP1 chimeric antibody-vcMMAE conjugate on mouse body weight
- Figure 7b Inhibitory effect of anti-CDCP1 chimeric antibody-vcMMAE conjugate on tumor growth in mice.
- the molecular biology experimental methods and immunoassay methods used in the present invention basically refer to J. Sambrook et al., Molecular Cloning: Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press, 1989, and The method was carried out according to the method described in F.M. Ausubel et al., Compiled Experimental Guide to Molecular Biology, 3rd Edition, John Wiley & Sons, Inc., 1995; the use of restriction enzymes was in accordance with the conditions recommended by the product manufacturer.
- restriction enzymes was in accordance with the conditions recommended by the product manufacturer.
- Example 1 Antigen preparation of full-length extracellular domain antigen of human, cynomolgus monkey, rat and mouse CDCP1-C and human CDCP1-A and CDCP1-B
- CDCP1-C involved in this example refers to the full-length extracellular region (from N-terminal to C-terminal, taking human CDCP1 as an example, the amino acid sequence of positions 30 to 667);
- CDCP1-A refers to the distal membrane region of CDCP1, that is, N end (from the N end to the C end, taking human CDCP1 as an example, the amino acid sequence is 30 to 430);
- CDCP1-B refers to the juxtamembrane region of CDCP1, that is, the C end (from the N end to the C end, taking human CDCP1 as an example)
- the amino acid sequence at positions 343 to 667 the specific structure is shown in Figure 1.
- CDCP1 proteins In vitro expression of CDCP1 proteins from humans, cynomolgus macaques, rats, and mice.
- the gene number of the human CDCP1 protein coding sequence is NP_073753.3
- the gene number of the cynomolgus macaque CDCP1 protein coding sequence is XP_001114659.2.
- the gene number of the mouse CDCP1 protein coding sequence is NP_001100339
- the gene number of the mouse CDCP1 protein coding sequence is AAH85253.
- the corresponding full-length extracellular region, far-membrane region or juxtamembrane region fragment is cloned into the expression vector pTT5, transfected and expressed in HEK-293T cells, and then purified using Fc/his tag, SEC or SDS Purity and molecular weight were detected by PAGE. The purity was greater than 95% and the endotoxin content was less than 1 EU/mg.
- HuCDCP1-Fc, HuCDCP1-A, HuCDCP1-B, HuCDCP1-C, CynoCDCP1, RatCDCP1 and MsCDCP1 were prepared for later animal immunization or screening. experiment.
- mice were immunized with human CDCP1-Fc (HuCDCP1-Fc) expressed in Example 1, once every two weeks, and mouse serum was collected each time to detect the titer of anti-CDCP1 antibodies in the serum.
- mouse serum was collected each time to detect the titer of anti-CDCP1 antibodies in the serum.
- mouse spleen cells and SP2/0 cells for hybridoma fusion
- spread the hybridoma cells on a 96-well plate take the supernatant after 7-10 days
- human CDCP1-his Kaika Biotechnology (Shanghai) Co., Ltd., CDC -HM101
- MDA-MB-231 cells breast cancer cells that highly express CDCP1, Nanjing Kebai, CBP60382
- Anti-mFc secondary antibody incubation PE Goat anti-mouse IgG (minimal x-reactivity) Antibody,
- the cells in the group without hybridoma supernatant and only the secondary antibody were used as a control.
- Geo-MFI detection sample
- Gao-MFI control
- 298 hybridoma monoclonal antibodies were selected with a concentration greater than 100 times.
- the screened hybridoma monoclonal antibodies are subjected to antibody endocytosis testing, and hybridoma monoclonal antibodies with an endocytosis rate greater than 50% in 1 hour are selected, and the molecules are sorted through subcloning, affinity testing, and sequencing, and finally Thirty-three hybridoma monoclonal antibodies were selected as candidate antibodies.
- the HuCDCP1-A, HuCDCP1-B, HuCDCP1-C, CynoCDCP1, MsCDCP1, and RatCDCP1 antigens (2 ⁇ g/ml) prepared in Example 1 were used for fixed detection respectively.
- the candidate antibody and control antibody CDSEQ135 obtained in Example 2 (derived from patent WO2011023389A1 Sequence No. 135, SEQ135 and antibody 135 described in the application of the present invention are all CDSEQ135 (unless otherwise specified).
- the binding conditions were determined by Caterra or Biacore makes the antibody to be detected (the antibody is diluted to the highest concentration of 150nM, diluted 3 times to 5 concentration points, respectively 1.85, 5.55, 16.67, 50, 150nM) through the detection chip respectively, and the data is analyzed through the corresponding software.
- the test results are shown in Table 2.
- the 13 anti-CDCP1 mouse monoclonal antibodies have good affinity with HuCDCP1-A, HuCDCP1-B, HuCDCP1-C, CynoCDCP1, MsCDCP1 or RatCDCP1.
- MDA-MB-231 (breast cancer cells that highly express CDCP1, Nanjing Kebai, CBP60382), PC3 (prostate cancer cells that highly express CDCP1, Nanjing Kebai, CBP60343), MCF7 (breast cancer cells that do not express CDCP1, Nanjing Kebai) Bai, CBP60380) and A2780 (human ovarian cancer cells that do not express CDCP1, Nanjing Kebai, CBP60283) were digested with 5mM EDTA, centrifuged, and 2.0 ⁇ 10 ⁇ 4 tumor cells were added to each well, and 50 ⁇ L (PBS+2% FBS ), and blocked with Fc blocker (Human TruStain FcX TM , Biolegend, 422302) for 10 mins at room temperature, added anti-CDCP1 mouse monoclonal antibody with a final concentration of 200 nM, diluted 3 times to 8 concentrations, and incubated at 4°
- the test results are shown in Table 3.
- the 11 anti-CDCP1 mouse monoclonal antibodies showed good affinity to MDA-MB-231 and PC3 tumor cells with high CDCP1 expression. Does not bind to MCF7 and A2780 tumor cells that do not express CDCP1.
- the test results are shown in Table 4.
- the mouse monoclonal antibodies in the table, MDA-MB-231 and PC3 all showed good endocytosis effects.
- mice were immunized with the antigen human CDCP1-Fc expressed in Example 1, once every two weeks, and the mouse serum was collected each time to detect the anti-CDCP1-his antibody titer in the serum.
- the Mouse spleen the spleen was processed using a commercially available kit (EasySep TM Mouse Pan-B Cell Isolation Kit, Stem Cell, 19844), cells were counted, and B220 (B cell marker, PE anti-mouse/human CD45R/B220Antibody, BioLegend, 103207) and CDCP1 were fluorescently labeled, and flow cytometry was used to sort B220+CDCP1+ cells, and then labeled by 10x Genomics kit (Chromium Next GEM Single Cell 5'Kit v2, 16rxns, 10X GENOMICS, PN-1000263) , single-cell BCR sequencing, in vitro data analysis, VH and VL sequence classification
- the candidate antibodies obtained in Example 6 were gene cloned and constructed into expression vectors for small-scale expression in CHO cells, and purified using an Fc affinity column (AT Protein A Diamond Plus Cat. No.: AA402312). Antibody purity was analyzed by HPLC and antibody purity was determined by Nanodrop. , Caterra conducts high-throughput affinity testing of small quantities of antibodies Certainly.
- human CDCP1 antigen (2 ⁇ g/ml) was used to fix and detect antibody binding, and Caterra was used to dilute the antibody to be detected (the antibody was diluted to the highest concentration of 150 nM, 3 times diluted to 5 concentration points, respectively 1.85, 5.55, 16.67, 50, 150nM) flowed through the detection chip respectively, and data analysis was performed through Kinetics software.
- 2 ⁇ g/ml antigen human CDCP1-C and 2 ⁇ g/ml human CDCP1-B were used for coating, and the antigen-antibody binding ability was tested by ELISA for verification.
- the test results are shown in Table 5.
- the anti-CDCP1 mouse monoclonal antibody in the table shows good affinity to HuCDCP1-C.
- Example 8 Detection of the binding ability of anti-CDCP1 antibodies to tumor cells using single B cell technology
- MDA-MB-231 cells were digested with 5mM EDTA, centrifuged and counted. Resuspend the cells in FACS buffer (PBS+2% FBS). Adjust the cell density to 4 ⁇ 10 ⁇ 5/ml. Add 50 ⁇ L (2 ⁇ 10) to each well. ⁇ 4 tumor cells), add Fc blocker (Human TruStain FcX TM , Biolegend, 422302) for blocking at room temperature for 10 mins, then add the antibody to be tested at a final concentration of 1.5 ⁇ g/ml, incubate at 4°C for 30 mins, centrifuge, and wash. , add secondary antibody (PE anti-human IgG Fc Antibody, Biolegend, 410708) for incubation, and then detect by flow cytometry, using Geo-MFI as the preliminary judgment standard for antibody cell binding.
- Fc blocker Human TruStain FcX TM , Biolegend, 422302
- SB1 ⁇ 15 and SB17 have good binding ability to MDA-MB-231 cells.
- the anti-CDCP1 mouse monoclonal antibody obtained in Example 2 and the single B cell technology anti-CDCP1 antibody obtained in Example 6 were subcloned and cultured. 5000-1000 monoclonal cells were centrifuged and passed through the TaKaRa MiniBEST Universal RNA Extraction Kit (TAKARA , cat#:9767) for small sample RNA extraction, extract RNA and reverse transcribe into cDNA through PrimeScript TM IV 1st strand cDNA Synthesis Mix (TAKARA, cat#6215A), use VH and VL primers for PCR amplification, and connect to pTT5 vector, and then pick 5-10 clones for DNA sequencing. Analyze the sequencing results, define the CDR region, locate the IgG family genes, distinguish each antibody family, and classify each antibody. The variable region and CDR sequences of the anti-CDCP1 mouse monoclonal antibody obtained are shown in Table 7:
- the mouse antibody sequence is compared with the human germline antibody amino acid sequence to find a sequence with high homology and better physical and chemical properties as the humanized antibody framework sequence; the mouse antibody CDR region is defined according to IMGT, and The mouse antibody CDR region is transplanted onto the human antibody framework sequence; based on sequence analysis and 3D simulation, part of the CDR and framework region amino acids are restored, as well as amino acids that may interact with the antibody surface; further computer calculations of mutation energy, best-single mutation, germline substitution, frequent reside substitution, etc. Each antibody generates 12 mutants for preliminary affinity testing.
- Antibodies with high affinity and humanization are further expressed and tested for multiple genus antigens, cell binding ability and endocytosis.
- the 12 humanized antibodies produced by 8C9 are: 1CP-151 ⁇ 1CP-162; the 12 humanized antibodies produced by 8E5 are: 1CP-112 ⁇ 1CP-123; the 12 humanized antibodies produced by 3C11 are: 1CP-124 ⁇ 1CP-135.
- mice monoclonal antibodies 3C11, 8E5 and 8C9 are shown in Table 8:
- the humanized anti-CDCP1 antibody obtained in Example 11 was gene cloned and constructed into the pTT5 expression vector for small-scale expression in CHO cells (Expi-CHOS: Gibco A29127), and an Fc affinity column (AT Protein A Diamond Plus Catalog No.: AA402312) was used. Purification, antibody purity analysis by HPLC, antibody purity determination by Nanodrop, and high-throughput affinity determination of small amounts of antibodies by Caterra. Specifically, the HuCDCP1-C antigen (2 ⁇ g/ml) was used to fix and detect the binding of the antibody.
- the antibody to be detected (antibody was diluted to the highest concentration of 150 nM, diluted 3 times to 5 concentration points, respectively, 1.85, 5.55, 16.67, 50, 150nM) flowed through the detection chip respectively, and data analysis was performed through Kinetics software.
- the test results are shown in Table 10.
- the anti-CDCP1 humanized antibody in the table shows good affinity to HuCDCP1-C.
- anti-CDCP1 humanized antibodies were selected for expression, and then the affinities of the antibodies with Hu-CDCP1-A, Hu-CDCP1-B, Cyno-CDCP1, and Ms-CDCP1 antigens were detected according to the above affinity detection method. It can be seen that the antibodies in Table 11 have good affinity to human and monkey CDCP1, and some antibodies show the binding ability of mouse CDCP1.
- Example 4 take MDA-MB-231 cells, digest the cells with 5mM EDTA, add 2 ⁇ 10 ⁇ 4 tumor cells to each well, add 50 ⁇ L (PBS+2% FBS), and proceed to room temperature through Fc blocker. Block for 10 mins, then add anti-CDCP1 humanized antibody with a final concentration of 200nM, after 3-fold gradient dilution, 8 concentrations, incubate at 4°C for 30 mins, centrifuge, wash, and add secondary antibody (PE anti-human IgG Fc Antibody, Biolegend, 410708), and then detected by flow cytometry. Geo-MFI (geometric mean fluorescence signal value) was used as the preliminary signal for antibody cell binding. Curve fitting was performed through graphpad to calculate the binding ability of the antibody and cells. It can be seen from the results in Table 12 that the humanized antibodies in Table 12 have good cell binding ability to MDA-MB-231.
- Example 5 to detect the endocytosis ability of the anti-CDCP1 humanized antibody.
- the test results are shown in Table 13.
- the humanized antibody has good endocytosis effect at the cellular level.
- Example 15 Laser confocal detection of antibody internalization in tumor cell lines
- HCC1806 High Express breast cancer cells
- Red fluorescence is used to label lysosomes, and by detecting the relative position changes and co-localization of green fluorescence and red fluorescence in cells, it can be determined whether the antibody co-localizes with lysosomes after endocytosis into cells.
- the antibody results detected in this experiment are consistent with the results shown in Figure 3, indicating that the detected antibodies can obviously bind to the cell surface, which is consistent with the detection of antibody binding to cells by flow cytometry.
- the green fluorescence signal in the cell gradually strengthens, indicating that the green fluorescence signal on the cell surface gradually transfers into the cell and the antibody is internalized.
- the orange fluorescence signal gradually strengthens (the superposition of green and red signals, indicated by arrows), indicating that the antibody After internalization, it enters lysosomes. Therefore, the antibodies provided by the present invention can enter lysosomes through tumor cell endocytosis.
- 3000 cells (breast cancer MDA-MB-231, prostate cancer PC-3 cells)/well were plated in a 96-well plate overnight, and antibodies with a final concentration of 500nM to 0.00128nM (100nM to 0.000256nM, respectively 100, 20, 4, 0.8, 0.16, 0.032, 0.0064, 0.00128, 0.000256nM), 5-fold dilution, 9 detection concentrations, placed in 37°C, CO 2 incubator for 96 hours, discard half of the culture medium (100 ⁇ L), Add 100 ⁇ L of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, cat#G7570) and detect the signal value on a BMG microplate reader.
- 500nM to 0.00128nM 100, 20, 4, 0.8, 0.16, 0.032, 0.0064, 0.00128, 0.000256nM
- 5-fold dilution 9 detection concentrations
- the graph was fitted using graphpad to calculate the inhibition of tumor cell growth by the antibody.
- this study tested the migration ability of tumor cells based on the transwell experiment.
- the specific cell migration experiment is to culture and collect MDA-MB-231 cells, wash them once with PBS, adjust the density to 8 ⁇ 10 ⁇ 5 cells/mL, and add the antibody to be detected to the cells to make the working concentration 10 ⁇ g/ml.
- the results are shown in Figure 4c.
- the tested antibodies 38E11, 14A10C5, 5B8, 10D2, 8C9, G10F6, 8E5, 3C11, 3B12H5 and 6A7 have better ability to inhibit the migration of tumor cells than SEQ135, thus causing tumor migration related Potential side effects are less severe.
- Anti-CDCP1 chimeric antibodies were conjugated to MMAE via a vc linker.
- the vc-MMAE structure is as follows:
- the vc connection substructure is as follows:
- the specific operation is to reduce each antibody and the control antibody CD27H10 (27H10 antibody in WO2018112334A1) with 2 times the molar amount of p-trichloroethyl phosphate (TECP) at 4°C for 1 hour. Then add 7 times the mole Ligation was carried out with an amount of vcMMAE at 4-25°C for 1 hour, then the reaction mixture was dialyzed against 1x PBS pH 8.0 and filter sterilized. The drug:antibody ratio (DAR) was tested for hydrophobic kurtosis using HLPC, and the molecular coupling results are shown in Table 14.
- Example 18 Analysis of in vitro killing of cancer cells by chimeric antibody-vcMMAE conjugates
- Colorectal cancer cells HCT116 (Nanjing Kebai, CBP60028), breast cancer cells MDA-MB-231 (Nanjing Kebai, CBP60382), prostate cancer cells PC3 (Nanjing Kebai, CBP60343) expressing CDCP1, and those not expressing CDCP1 were used.
- MCF7 cells (Nanjing Kebai, CBP60380) were used to detect the cell killing activity of chimeric antibody ADC molecules.
- the specific steps are: count colorectal cancer cells HCT116, breast cancer cells MDA-MB-231, prostate cancer cells PC3, and MCF7 cells respectively, adjust to 3000 cells/well, and spread them in a 96-well plate overnight; add even
- the final concentration of the conjugate is 8nM to 0.000512nM (5-fold dilution, 7 detection concentrations), a total of 200 ⁇ L, placed in a 37°C, CO2 incubator for 120 hours, discard half of the culture medium (100 ⁇ L), and add 100 ⁇ L CellTiter- Glo Luminescent Cell Viability assay reagent (Promega, cat#G7570) was used to detect the signal value on a BMG microplate reader. According to the signal value and antibody concentration, graphpad was used to fit the graph and the inhibitory activity of the antibody on tumor cell growth was calculated. The results are shown in Figure 5 and Table 15.
- Example 19 Chimeric antibody-vcMMAE conjugate inhibits tumor growth of human colorectal cancer cell HCT116 in mouse model
- mice 150 BALB/c nude mice were adapted to the laboratory environment for 3-7 days. HCT116 cells were resuspended in McCoy's 5a medium to 5 ⁇ 10 6 cells, and then 0.1 mL per mouse was subcutaneously inoculated into the experimental mice on the right rear back, and tumor growth was observed regularly. When the mice's tumors grow to an average volume of about 150-200 mm, they are randomly divided into groups according to tumor size, with 8 mice in each group, to ensure that the tumor volumes and mouse weights between different groups are similar. The grouping day is defined as Day1.
- routine monitoring includes tumor growth and the effects of drugs on the normal behavior of animals, such as the activity of experimental animals, food and water intake, weight gain or loss, eyes, coat, feces and other abnormalities during the experiment. Observed clinical symptoms were recorded in the raw data. After the start of drug administration, the body weight and tumor size of the mice were measured twice a week.
- the ICP152 antibody and the control antibody CD27H10 were connected to vc-MMAE according to the method in Example 18, with a target DAR of 4, and then the physical and chemical properties of the molecules were detected and analyzed respectively.
- the specific analysis method is:
- the UNcle multifunctional protein stability analysis system was used to detect the denaturation temperature (Tm value), aggregation temperature (Tagg value) and hydration kinetic diameter of ADC molecules.
- Tm value denaturation temperature
- Tagg value aggregation temperature
- hydration kinetic diameter of ADC molecules.
- SLS static light scattering
- DLS dynamic light scattering
- the peak area normalization method is used to quantitatively analyze the results. If automatic integration fails due to baseline drift, retention time changes, peak shape changes, etc., the integration parameters should be adjusted or the spectrum should be manually integrated.
- the main peak (MP) is the monomer peak
- the peak with the retention time before the main peak is the polymer peak (HMW)
- the retention time after the main peak is the low molecular impurity peak (LMW).
- Tm represents the temperature at which 50% of the protein molecules unfold during the heating denaturation process, characterizing the conformational stability of the molecule. It can be seen from the comparison of results that the Tm values of ICP152-MMAE and CD27H10-MMAE are similar. It shows that the conformational stability of the two is equivalent.
- Tagg represents the starting temperature when protein molecules aggregate, characterizing the colloidal stability of the protein. From the data in Table 16, it can be seen that the Tag value of 1CP152-MMAE is 64.1°C, and the Tag value of CD27H10-MMAE is 60.1°C. The Tag value of the two differs by 4°C.
- 1CP152-MMAE and CD27H10-MMAE molecules were placed at 2 to 8°C for different times (0 days, 3 days, and 5 days) to examine the changes in their purity. As shown in Table 17, the purity of 1CP152-MMAE did not change after being placed at 2-8°C for 5 days; the purity of CD27H10-MMAE was reduced by 0.5% after being placed at 2-8°C for 5 days; indicating that 1CP152-MMAE has better long-term storage stability.
- Example 21 Analysis of in vitro killing of cancer cells by anti-CDCP1 humanized antibody-vcMMAE conjugates
- the humanized antibodies ICP125, ICP117 and ICP152 were subjected to ADC ligation, and the ligation process was the same as in Example 18.
- the molecular coupling results are shown in Table 18.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Sont divulgués un anticorps anti-CDCP1 ou un fragment de liaison à l'antigène de celui-ci, une molécule d'acide nucléique codant pour celui-ci, et un procédé de préparation associé. L'anticorps anti-CDCP1 ou le fragment de liaison à l'antigène de celui-ci a une capacité de liaison à une cible, une capacité de liaison de cellule tumorale, une capacité d'endocytose, une capacité à inhiber la migration de cellules tumorales, et une pharmacopotentialité. Est divulgué en outre un conjugué de l'anticorps ou du fragment de liaison à l'antigène de celui-ci. Sont divulgués également une composition pharmaceutique comprenant l'anticorps ou le fragment de liaison à l'antigène de celui-ci, et son utilisation dans la préparation d'un médicament pour la prévention et/ou le traitement d'une maladie liée à CDCP1, telle qu'une tumeur.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210700116.0 | 2022-06-20 | ||
CN202210700116 | 2022-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023246701A1 true WO2023246701A1 (fr) | 2023-12-28 |
Family
ID=89379139
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/101086 WO2023246701A1 (fr) | 2022-06-20 | 2023-06-19 | Anticorps et son utilisation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023246701A1 (fr) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007112734A (ja) * | 2005-10-19 | 2007-05-10 | Chugai Pharmaceut Co Ltd | 抗cdcp1抗体を含有する癌細胞増殖抑制剤 |
CA2770141A1 (fr) * | 2009-08-28 | 2011-03-03 | F. Hoffmann-La Roche Ag | Anticorps contre cdcp1 destines au traitement du cancer |
CA2770161A1 (fr) * | 2009-08-28 | 2011-03-03 | Roche Glycart Ag | Anticorps anti-cdcp1 humanises |
WO2015082446A1 (fr) * | 2013-12-02 | 2015-06-11 | F. Hoffmann-La Roche Ag | Traitement du cancer à l'aide d'un anticorps anti-cdcp1 et d'un taxane |
WO2018112334A1 (fr) * | 2016-12-16 | 2018-06-21 | Bluefin Biomedicine, Inc. | Anticorps anti-protéine 1 contenant un domaine anti-cub (cdcp1), conjugués anticorps-médicament et leurs méthodes d'utilisation |
US20220119545A1 (en) * | 2018-11-09 | 2022-04-21 | Beth Israel Deaconess Medical Center | Cdcp1-targeted therapies |
-
2023
- 2023-06-19 WO PCT/CN2023/101086 patent/WO2023246701A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007112734A (ja) * | 2005-10-19 | 2007-05-10 | Chugai Pharmaceut Co Ltd | 抗cdcp1抗体を含有する癌細胞増殖抑制剤 |
CA2770141A1 (fr) * | 2009-08-28 | 2011-03-03 | F. Hoffmann-La Roche Ag | Anticorps contre cdcp1 destines au traitement du cancer |
CA2770161A1 (fr) * | 2009-08-28 | 2011-03-03 | Roche Glycart Ag | Anticorps anti-cdcp1 humanises |
WO2015082446A1 (fr) * | 2013-12-02 | 2015-06-11 | F. Hoffmann-La Roche Ag | Traitement du cancer à l'aide d'un anticorps anti-cdcp1 et d'un taxane |
WO2018112334A1 (fr) * | 2016-12-16 | 2018-06-21 | Bluefin Biomedicine, Inc. | Anticorps anti-protéine 1 contenant un domaine anti-cub (cdcp1), conjugués anticorps-médicament et leurs méthodes d'utilisation |
US20200181281A1 (en) * | 2016-12-16 | 2020-06-11 | Bluefin Biomedicine, Inc. | Anti-cub domain-containing protein 1 (cdcp1) antibodies, antibody drug conjugates, and methods of use thereof |
US20220119545A1 (en) * | 2018-11-09 | 2022-04-21 | Beth Israel Deaconess Medical Center | Cdcp1-targeted therapies |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2020135201A1 (fr) | Anticorps et son utilisation | |
US10266593B2 (en) | Human CD3 binding antibody | |
RU2693661C2 (ru) | Антитело против pdl-1, его фармацевтическая композиция и применение | |
JPWO2020138489A1 (ja) | 新規抗ccr8抗体 | |
WO2020082209A1 (fr) | Anticorps anti-cldn28.2 et ses applications | |
WO2021228141A1 (fr) | Conjugué anticorps-médicament, son procédé de préparation et son utilisation | |
EP4039704A1 (fr) | Anticorps anti-pd-1 et son utilisation | |
CN110799546A (zh) | 重组双特异性抗体 | |
WO2022068810A1 (fr) | Anticorps bispécifique anti-claudine 18.2 et cd3 et son utilisation | |
EP4421095A1 (fr) | Nanocorps anti-mésothéline et leur utilisation | |
CN117083301A (zh) | 特异性识别磷脂酰肌醇蛋白聚糖3的单克隆抗体及其应用 | |
US20210277139A1 (en) | Ifn-gamma-inducible regulatory t cell convertible anti-cancer (irtca) antibody and uses thereof | |
WO2022179466A1 (fr) | Anticorps anti-siglec15 et utilisation associée | |
WO2023246701A1 (fr) | Anticorps et son utilisation | |
WO2022116079A1 (fr) | Anticorps anti-ceacam5 humanisé et son procédé de préparation et son utilisation | |
KR20230154317A (ko) | 항-cldn6 항체 및 이의 용도 | |
WO2024007671A1 (fr) | Anticorps se liant spécifiquement à cd24 et son utilisation | |
WO2024131849A1 (fr) | Anticorps monoclonal cd38 et son utilisation | |
WO2024114525A1 (fr) | Protéine de liaison b7-h3 et son utilisation | |
WO2023216218A1 (fr) | Anticorps se liant de manière spécifique à cd22, son procédé de préparation et son utilisation | |
WO2024113099A1 (fr) | Anticorps bispécifiques recombinants clivables par protéase et compositions et utilisations associées | |
WO2023186077A1 (fr) | Anticorps monoclonal anti-pd-1, son dérivé et son utilisation | |
WO2022188652A1 (fr) | Protéine de liaison à ror1 et son utilisation | |
WO2024017281A1 (fr) | Anticorps multispécifique et son utilisation | |
EP4293047A1 (fr) | Anticorps anti-pd-l1 et son utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23826349 Country of ref document: EP Kind code of ref document: A1 |